Summary of Evidence

Digital Rectal Examination and Prostate-Specific Antigen

Benefits

The evidence is insufficient to determine whether screening for prostate cancer with prostate-specific antigen (PSA) or digital rectal exam (DRE) reduces mortality from prostate cancer. Screening tests are able to detect prostate cancer at an early stage, but it is not clear whether this earlier detection and consequent earlier treatment leads to any change in the natural history and outcome of the disease. Observational evidence shows a trend toward lower mortality for prostate cancer in some countries, but the relationship between these trends and intensity of screening is not clear, and associations with screening patterns are inconsistent. The observed trends may be due to screening, or to other factors such as improved treatment.[1] Results from two randomized trials show no effect on mortality through 7 years but are inconsistent beyond 7 to 10 years.

Harms

Based on solid evidence, screening with PSA and/or DRE detects some prostate cancers that would never have caused important clinical problems. Thus, screening leads to some degree of overtreatment. Based on solid evidence, current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men. The most common of these side effects are erectile dysfunction and urinary incontinence.[1-3] Whatever the screening modality, the screening process itself can lead to adverse psychological effects in men who have a prostate biopsy but do not have identified prostate cancer.[4] Prostatic biopsies are associated with complications, including fever, pain, hematospermia/hematuria, positive urine cultures, and rarely sepsis.[5]

Description of the Evidence

Study Design: Evidence obtained from cohort or case-control studies.

Internal Validity: Good.

Consistency: Good.

Magnitude of Effects on Health Outcomes: 20% to 70% of men who had no problems before radical prostatectomy or external-beam radiation therapy will have reduced sexual function and/or urinary problems.[1]

Significance

Incidence and Mortality

Prostate cancer is the most common cancer diagnosed in North American men, excluding skin cancers. It is estimated that in 2015, approximately 220,800
new cases and 27,540 prostate cancer-related deaths will occur in the United
States.[1] Prostate cancer is now the second leading cause of cancer death in
men, exceeded only by lung cancer. It accounts for 26% of all male cancers and
9% of male cancer-related deaths.[1] Age-adjusted incidence rates increased
steadily over the past several decades, with particularly dramatic increases associated with
the inception of widespread use of prostate-specific antigen (PSA) screening in the late
1980s and early 1990s, followed by a more recent fall in incidence. Between 2007 and 2011, mortality rates decreased by 3.2% per year.[1] It has been suggested
that declines in mortality rates in certain jurisdictions reflect the
benefit of PSA screening,[2] but others have noted that these
observations may be explained by independent phenomena such as improved
treatment effects.

Regional differences have been observed in prostate cancer incidence and mortality rates and in rates of radical prostatectomy. Until 1989, the increased
incidence was most likely the result of increased tumor detection due to increasing rates of transurethral prostatectomy.[3,4] Subsequent
increases were most likely the result of widespread use of PSA testing for early detection and
screening.[5,6] Variable incidence rates may reflect variability in the
intensity of early detection practices across the United States and other
jurisdictions. While differences in aggregate mortality by regions of the
United States have not been observed, considerable variation in mortality rates
between African American and white men are seen.[7,8] (Refer to the Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality section of this summary for more information.)

Risk Factors

Prostate cancer is uncommonly seen in men younger than 50 years; the
incidence rises rapidly with each decade thereafter. The incidence rate is higher in African American men than in white men. From 2005 to 2009, the overall age-adjusted incidence rate was 236 per 100,000 for African American men and 146.9 per 100,000 for white men.[9] African American males have a higher
mortality from prostate cancer, even after attempts to adjust for
access-to-care factors.[10] Men with a family history of prostate cancer are
at an increased risk of the disease compared with men without this history.[11,12]
Other potential risk factors besides age, race, and family history of prostate
cancer include alcohol consumption, vitamin or mineral interactions, and other
dietary habits.[13-17] A significant body of evidence suggests that a diet high in fat, especially saturated fats and fats of animal origin, is associated with a higher risk of prostate cancer.[18,19] Other possible dietary influences include selenium, vitamin E, vitamin D, lycopene, and isoflavones. (Refer to the PDQ summary on Prostate
Cancer Prevention for more information.) Evidence from a nested case-control study within the
Physicians’ Health Study,[20] in addition to a case-control study [21] and a retrospective review of screened prostate cancer patients,[22] suggests that higher plasma insulin-like growth
factor-I levels may be associated with a higher prostate cancer risk.[23] Not all studies, however, have confirmed this association.[24]
The estimated lifetime risk of diagnosis of prostate cancer is about 16.5%,[25] and the lifetime risk of dying from this disease is 2.8%.[26]

The biology and natural history of prostate cancer is not completely understood. Rigorous evaluation of any prostate cancer screening modality is desirable because the natural history of the disease is variable, and appropriate treatment is not clearly defined. Although the prevalence of prostate cancer and preneoplastic lesions found at
autopsy steadily increases for each decade of age, most of these lesions remain
clinically undetected.[27]
An autopsy study of white and Asian men also found an increase in occult prostate cancer with age, reaching nearly 60% in men older than 80 years. More than 50% of cancers in Asian men and 25% of cancers in white men had a Gleason score of 7 or greater, suggesting that Gleason score may be an imprecise indicator of clinically insignificant prostate cancer.[28]

There is an association between primary tumor volume and
local extent of disease, progression, and survival.[29] A review of a large
number of prostate cancers in radical prostatectomy, cystectomy, and autopsy
specimens showed that capsular penetration, seminal vesicle invasion, and lymph
node metastases were usually found only with tumors larger than 1.4 cc.[30]
Furthermore, the semiquantitative histopathologic grading scheme proposed by
Gleason is reasonably reproducible among pathologists and correlates with the
incidence of nodal metastases and with patient survival in a number of reported
studies.[31]

Cancer statistics from the American Cancer Society and the National Cancer
Institute indicated that between 2002 and 2008, the proportion of disease diagnosed at a
locoregional stage and at a distant stage was 93% and 4% for whites, compared with 91%
and 6% for African Americans, respectively.[9] Stage distribution of prostate cancer is affected
substantially by the intensity of early detection efforts.

Pathologic stage does not always reflect clinical stage and upstaging (owing
either to extracapsular extension, positive margins, seminal vesicle invasion, or
lymph node involvement) occurs frequently. Of the prostate cancers detected by
digital rectal exam (DRE) in the pre-PSA era, 67% to 88% were at a
clinically localized stage (T1–2, NX, M0 [T = tumor size, N = lymph node involvement, and M = metastasis]).[32,33] However, in one of those series
of 2,002 patients undergoing annual screening DRE, only
one-third of men proved to have pathologically organ-confined disease.[33]

With the proliferation of PSA for early detection, reviews of large numbers of
asymptomatic men with prostate cancer found that most have organ-confined disease. One study found
that 63% of cancers detected in men undergoing their first screening PSA were
pathologically organ-confined cancers; the percentage increased to 71% if
cancer was detected on a subsequent examination.[34] In a series of 2,999 men
undergoing screening with PSA, DRE, and transrectal ultrasound, 62% of the
tumors detected were reported to be pathologically organ-confined.[35] While
the proportion of node-positive cancers in the pre-PSA era were in the range of
25% for patients with ostensibly localized disease, current series report
proportions as low as 3%.[36] Stage T1c tumors detected by serial PSA and
removed by radical prostatectomy are organ-confined in 79% of cases.[37]

Survival rates for prostate cancer have improved from 1974 to the present.
Lead-time and length-bias effects of early detection and the possible influence
of stage migration must also be considered when trends in survival
data are interpreted.[38] Reported survival rates may also vary, depending on whether the analytical methods reflect crude disease-specific rates (absolute
disease-specific survival) or take into account competing risks for the given
age group (relative disease-specific survival).

Evidence of Benefit

Before the 1990s, the digital rectal examination (DRE) was the test
traditionally used for prostate cancer screening. Two other procedures are also available: transrectal ultrasound (TRUS) imaging and serum prostate-specific antigen (PSA) concentrations.[1] Prostate cancer screening is controversial
because of the lack of definitive evidence of benefit. A small randomized trial in Sweden evaluated the effects of screening men aged 50 to 69 years every 3 years; the first two screenings included DRE only, followed by two screenings with DRE combined with a test for PSA. The trial was not powered to detect even moderate differences in prostate cancer mortality, which was the same in the two groups: 1.3% (20 of 1,494 patients) for men assigned to screening and 1.3% (97 of 7,532 patients) for controls.[2]
The controversy persists. A nested case-control study was conducted at ten U.S. Department of Veterans Affairs (VA) medical centers in New England (71,661 patients receiving ambulatory care between 1989 and 1990), identifying 501 patients who were diagnosed with adenocarcinoma of the prostate from 1991 to 1995 and who died between 1991 and 1999. Controls were selected from among patients living at the time case patients died (matched 1:1 for age and VA facility). A benefit from screening by PSA or PSA and/or DRE was not found for PSA (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.71–1.64; P = .72) or for PSA and/or DRE (OR, 1.13; 95% CI, 0.63–2.06; P = .68). Because prostate cancer has a relatively slow course, it is possible that the relatively short follow-up period in this study precluded the observation of a benefit, which might accrue only after 10 or more years from the time of screening.[3]

Adding to the controversy
is the lack of consensus regarding optimal treatment of localized disease and
the clear evidence that active treatment options are associated with
significant morbidity. Treatment options for early-stage disease include
radical prostatectomy, definitive radiation therapy, and watchful waiting (no
immediate treatment; treatment if indications of progression are present, but treatment not designed with curative intent). Multiple series from various years and institutions have been
reported on the outcomes of patients with localized prostate cancer who
received no treatment but were followed with surveillance alone. Outcomes have
also been reported for active treatments, but valid comparisons of efficacy
between surgery, radiation, and watchful waiting are seldom
possible because of differences in reporting and selection factors in the
various reported series. A randomized trial in Scandinavian men published in 2002 explored the benefit of radical prostatectomy over watchful waiting in men with newly diagnosed, well-differentiated, or moderately well-differentiated prostate cancers of clinical stages T1b, T1c, or T2.[4] Six hundred ninety-eight men younger than 75 years, most with clinically detected rather than screen-detected cancers (unlike most newly diagnosed patients in North America) were randomly assigned to the two-arm trial. After 5 years of follow-up, the difference in prostate cancer-specific mortality between radical prostatectomy and watchful waiting groups was 2%; after 10 years of follow-up, the difference was 5.3% (relative risk [RR], 0.56 [0.36–0.88]). There was also a difference of about 5% in all-cause mortality that was apparent only after 10 years of follow-up (RR, 0.74 [0.56–0.99]). Thus 20 men with palpable, clinically localized prostate cancer would require radical prostatectomy rather than watchful waiting to extend the life of one man. Because most prostate cancers that are detected today with PSA screening are not palpable, this study may not be directly generalizable to the average newly diagnosed patient in the United States.[5]

A Swedish retrospective study of a nationwide cohort of patients with localized prostate cancer aged 70 years or younger reported that 10-year prostate cancer-specific mortality was 2.4% among men diagnosed with clinically local stage T1a, T1b, or T1c, with a serum PSA of less than 10 ng/mL, and with a Gleason score of 2 to 6, referred to as low-risk cases, of which there were 2,686.[6] This subgroup analysis was derived from a cohort study of 6,849 men diagnosed between January 1, 1997 and December 31, 2002, aged 70 years or younger, who had local stage T1 to T2 with no signs of lymph node metastases or bone metastases, and a PSA serum level of less than 20 ng/mL, as was abstracted from the Swedish Cancer Registry, which captured 98% of solid tumors among men aged 75 years or younger. Cohort treatment options were surveillance (n = 2,021) or curative intent by radical prostatectomy (n = 3,399) or radiation therapy (n = 1,429), which were to be determined at the discretion of treating physicians. Surveillance or expectancy treatment was either active surveillance with curative treatment if progression occurred or watchful waiting—a strategy for administering hormonal treatment upon symptomatic progression. Using all-cause mortality as the benchmark, the study calculated cumulative incidence mortality for the three treatment groups of the entire cohort and the low-risk subgroup. Surveillance was more common among men with high comorbidity and among men with low-risk tumors. The 10-year cumulative risk of death from prostate cancer for the entire 6,849 person cohort was 3.6% in the surveillance group and 2.7% in the curative-intent group compared with the low-risk surveillance group (2.4%) and the low-risk curative-intent group (0.7%). Biases inherent in treatment assignment could not be accounted for adequately in the analysis, which prevented conclusions about the relative effectiveness of alternative treatments. However, a 10-year prostate cancer-specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group suggested that surveillance may be a suitable treatment for many patients with low-risk disease compared with the 19.2% 10-year risk of death from competing causes observed in the surveillance group and 10.2% in the curative-intent group of the total 6,849 person cohort.[6]

Digital Rectal Exam

Although DRE has been used for many years, careful evaluation of this modality
has yet to take place. Several observational studies have examined process measures such as sensitivity and case-survival data,
but without appropriate controls and with no adjustment for lead-time and
length biases.[7,8]

In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up.[9] Thirty-eight of 43
patients with a palpable abnormality in the prostate agreed to undergo biopsy.
The positive predictive value (PPV) of a palpable nodule, i.e., prostate cancer on
biopsy, was 29% (11 of 38). Further evaluation revealed that 45% of the cases
were stage B, 36% were stage C, and 18% were stage D. More results from the
same investigators revealed a 25% positive predictive value, with 68% of the
detected tumors clinically localized but only approximately 30% pathologically
localized after radical prostatectomy.[10] Some investigators reported a high proportion of clinically localized disease when prostate cancer
is detected by routine rectal examination,[11] while others reported that even
with annual rectal examination, only 20% of cases are localized at
diagnosis.[12] It has been reported that 25% of men
presenting with metastatic disease had a normal prostate examination.[13]
Another case-control study examining screening with both DRE and PSA found a reduction in prostate cancer mortality that was not statistically significant (OR, 0.7; 95% CI, 0.46–1.1). Most men in this study were screened with DRE rather than PSA.[14] All four of these case-control studies are consistent with a reduction of 20% to 30% in prostate cancer mortality. Potential biases inherent in this study design, however, limit the ability to draw conclusions on the basis of this evidence alone.

Since PSA assays became widely available in the late 1980s, DRE alone is rarely discussed as a screening modality. A number of studies have found that DRE has a poor predictive value for
prostate cancer if PSA is at very low levels. In the European Study on
Screening for Prostate Cancer, it was found that if DRE is used only for a
PSA higher than 1.5 ng/mL (thus, no DRE is performed with PSA < 1.5 ng/mL), 29% of all
biopsies would be eliminated while maintaining a 95% prostate cancer detection
sensitivity. By applying DRE only for patients with a PSA higher than 2.0 ng/mL, the
biopsy rate would decrease by 36% while sensitivity would drop to only 92%.[15]
A previous report from this same institution found DRE to have poor performance
characteristics. Among 10,523 men randomly assigned to screening, it was
reported that the overall prostate cancer detection rate using PSA, DRE, and
TRUS was 4.5% compared with only 2.5% if DRE alone had been used. Among men
with a PSA lower than 3.0 ng/mL, the PPV of DRE was only
4% to 11%.[16] Despite the poor performance of DRE, a retrospective
case-control study of men in Olmsted County, Minnesota, who died of prostate
cancer found that case patients were less likely to have undergone DRE during
the 10 years before diagnosis of prostate cancer (OR, 0.51; 95%
CI, 0.31–0.84). These data suggested that screening DREs
may prevent 50% to 70% of deaths from prostate cancer.[17] Contrary to
these findings, results from a case-control study of 150 men who ultimately
died of prostate cancer were compared with 299 controls without disease. In this
different population, a similar number of cases and controls had undergone DRE
during the 10-year interval before prostate cancer diagnosis.[18] One
case-control study reported no statistically significant association between
routine screening with DRE and occurrence of metastatic
prostate cancer.[19]
The Prostate Cancer Prevention Trial (PCPT) requested all men undergo prostate biopsy at study end to address ascertainment bias; the sensitivity of DRE for prostate cancer was 16.7%. The sensitivity increased to 21.3% in men receiving finasteride.[20]

Rectal examination is inexpensive, relatively noninvasive, and nonmorbid and can be
taught to nonprofessional health workers; however, its effectiveness depends on
the skill and experience of the examiner. The possible contribution of routine annual screening by
rectal examination in reducing prostate cancer mortality remains to be determined.

Transrectal Ultrasound and Other Imaging Tests

Imaging procedures have been suggested as possible screening modalities for
prostate cancer. Prostatic imaging is possible by ultrasound, computed
tomography, and magnetic resonance imaging. Each modality has relative merits
and disadvantages for distinguishing different features of prostate cancer.
Ultrasound has received the most attention, having been examined by several
investigators in observational settings.[21] Sensitivity ranged from 71% to 92% for prostatic carcinoma and
60% to 85% for subclinical disease. Specificity values ranged from 49% to 79%,
and positive predictive values in the 30% range have been reported. The
sensitivity and positive predictive value for ultrasound as a single test may
be better than for rectal examination. The rate of cancer is extremely low among
ultrasound-positive patients in whom rectal and PSA examinations are normal.[22] TRUS is generally relegated to a role in the diagnostic work-up of an abnormal
screening test rather than in the screening algorithm. The cost and poor performance of other imaging
modalities have led to their elimination from all early detection algorithms.

Contemporary prostate biopsy relies on spring-loaded biopsy devices that are
either digitally guided or guided via ultrasound. TRUS
guidance is the most frequently used method of directing prostate needle biopsy because
there is some suggestion that the yield of biopsy is improved with such
guidance.[23] With the virtually simultaneous clinical acceptance of
TRUS, spring-loaded biopsy devices, and the proliferation of
PSA screening in the late 1980s, the number of prostate cores obtained from
patients with either an abnormal DRE or PSA was most commonly six, using a
sextant method of sampling the prostate.[24] There is evidence that the
predictable increase in cancer detection rates that would be expected by
increasing the number of biopsy cores beyond six does occur; e.g., biopsies with
12 or 15 cores would increase the proportion of biopsied men having cancer
detected by 30% to 35%.[25,26] The extent to which such increased detection
will reduce morbidity and mortality from the disease or increase the fraction
of men treated unnecessarily is unknown.

Prostate-Specific Antigen

The PSA test has
been examined in several observational settings for initial diagnosis of
disease, as a tool to monitor for recurrence after initial therapy, and for
prognosis of outcomes after therapy. There is no PSA value below which a man can be assured that he has no risk of prostate cancer. Parameter estimates for this test
include sensitivity in the range of 70%.[27]

In a review of the Prostate Cancer Prevention Trial, 2,950 men who never had a PSA level higher than 4.0 ng/mL or an abnormal DRE had a final PSA determination and underwent a prostate biopsy after being in the study for 7 years.[28] There was a 15.2% (n = 449) biopsy-proven prevalence of prostate cancer in men with PSA levels no higher than 4.0 ng/mL. High-grade prostate cancer (defined as Gleason score ≥7) was seen in 15.8% (n = 71) of these men. Size of the tumor was not reported.

In the placebo arm of the Prostate Cancer Prevention Trial, there was no cutpoint of PSA with simultaneous high sensitivity and high specificity for detection of prostate cancer in healthy men, but rather a continuum of prostate cancer risk at all values of PSA.[29]

The potential value of the test
appears to be in its simplicity, objectivity, reproducibility, relative lack of
invasiveness, and relatively low cost. PSA has increased the detection rate of
early-stage cancers, some of which may be curable by local-modality
therapies, but others of which do not require treatment.[30-33] Circumstantial evidence favoring screening for prostate
cancer is analogous to that for lung cancer screening in the 1950s and 1960s;
screening results in a shift to a higher proportion of cases with earlier-stage
cancers at diagnosis. This shift may result in mortality reduction. For
lung cancer, no mortality benefit resulted.[34] However, the possibility of identifying
an excessive number of false-positives in the form of benign prostatic lesions
requires that the test be evaluated carefully.
Furthermore, there is a risk of overdiagnosis and overtreatment (i.e., the detection of a histological malignancy that if left untreated would have had a benign or indolent natural history and would have been of no clinical significance).

A nested case-control
prospective study with 10 years of follow-up reported that a single elevated
PSA higher than 4.0 ng/mL predicted subsequent cancer with a sensitivity of
71% for the first 5 years and a specificity of 91% for the first 10 years of
follow-up. The cancers diagnosed were characterized by stage and grade to be
clinically important. Forty-two percent were extracapsular at diagnosis.[35]
Experience with repeat PSA screening suggests that tumors detected on follow-up
examinations are of lower clinical stage and grade.[36] Although a cutoff
value of 4.0 ng/mL is frequently used to prompt prostate biopsy, screening
studies have demonstrated that lowering the PSA cutoff will substantially
increase the number of cancers detected, particularly in African Americans.[37] In one study of the impact of race on PSA and tumor volume, these two variables were higher among African American men after adjustment for age, stage, pathologic stage, Gleason score, and volume of benign disease.[38] Furthermore,
lower cutoff PSA values are associated with a high proportion of
negative biopsies (false-positives).[39] An initial PSA lower than 2.5 ng/mL
is associated with a very low risk of cancer detection within a 4-year follow-up.[36,40]

Probably the largest PSA/DRE early diagnosis experience comes from the Prostate
Cancer Awareness Week program conducted at numerous sites around the United
States. A report from that program indicates that of 116,073 participating
men, if a 4.0 ng/mL PSA cutoff value was used, 22,014 men had an abnormal PSA,
DRE, or both.

Various methods to improve the performance of PSA in early cancer detection have been developed (see below). The proportion of men who have abnormal PSA test results that revert to normal after 1 year is high (65%–83%, depending on the method).[41] This is likely because of a substantial biological or other variability in PSA levels in individual men. Several variables can affect PSA levels in men. Besides normal biological fluctuations that appear to occur,[41,42] pharmaceuticals such as finasteride (which reduces PSA by approximately 50%) and over-the-counter agents such as PC-SPES (an herbal agent that appears to have estrogenic effects) can affect PSA levels.[43,44] Some authors have suggested that ejaculation and DRE can also affect PSA levels, but subsequent examination of these variables have found that they do not have a clinically important effect on PSA.[45] In any case, given this high variability, an elevated PSA should be confirmed by repeat testing before more invasive diagnostic tests are performed.

The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is a multicenter, randomized, two-armed trial designed to evaluate the effect of screening for prostate, lung, colorectal, and ovarian cancers on disease-specific mortality. From 1993 through 2001, 76,693 men at ten U.S. study centers were randomly assigned to receive annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and DRE for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended.

In the screening group, rates of compliance were 85% for PSA testing and 86% for DRE. Self-reported rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Results from the first four rounds of screening are shown in the Summary of First Four Prostate, Lung, Colorectal, and Ovarian Screening Rounds table.[46]

Summary of First Four Prostate, Lung, Colorectal, and Ovarian Screening Roundsa

After 7 years of follow-up, with vital status known for 98% of men, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group (rate ratio, 1.22; 95% CI, 1.16–1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75–1.70). The data at 10 years were 67% complete and consistent with these overall findings (incidence rate ratio, 1.17; 95% CI, 1.11–1.22 and mortality rate ratio, 1.11; 95% CI, 0.83–1.50). Thus, after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.

At 7 years, the total numbers of deaths (excluding those from prostate, lung, or colorectal cancers) were 2,544 in the screening group and 2,596 in the control group (rate ratio, 0.98; 95% CI, 0.92–1.03); at 10 years, the numbers of such deaths were 3,953 and 4,058, respectively (rate ratio, 0.97; 95% CI, 0.93–1.01). The distribution of the causes of death was similar in the two groups.

The following are several possible explanations for the lack of a reduction in mortality so far in this trial:

Annual screening with the PSA test using the standard U.S. threshold of 4 ng per mL and DRE to trigger diagnostic evaluation may not be effective.

The level of screening in the control group could have been substantial enough to dilute any modest effect of annual screening in the screening group.

Approximately 44% of the men in each study group had undergone one or more PSA tests at baseline, which would have eliminated some cancers detectable on screening from the randomly assigned population; thus, the cumulative death rate from prostate cancer at 10 years in the two groups combined was 25% lower in those who had undergone two or more PSA tests at baseline than in those who had not been tested.

Potentially, the most important explanation is that improvement in therapy for prostate cancer during the course of the trial probably resulted in fewer prostate-cancer deaths in the two study groups, which blunted any potential benefits of screening.

The follow-up may not be long enough for benefit from the earlier detection of an increased number of prostate cancers in the screening group to emerge.[47]

After a PSA finding greater than 4.0 ng/mL, within 1 year only 41% of men underwent prostate biopsy; within 3 years of this finding, only 64% of men underwent prostate biopsy. Such lower biopsy rates, associated with lower prostate cancer detection rates, may have blunted the impact of screening on mortality.[48]

Prostate cancer mortality data from the PLCO cancer screening trial after 13 years of follow-up show no reduction in mortality due to prostate cancer screening with PSA and DRE.[49] Organized screening in the intervention arm of the trial did not produce a mortality reduction compared with opportunistic screening in the control arm. There were no apparent interactions with age, baseline comorbidity, or pre-trial PSA testing as hypothesized in an intervening analysis by a subgroup analysis. These results are consistent with the prior report at 7 to 10 years of follow-up described above.[47] The update accounts for 76,685 men, aged 55 to 74 years, enrolled at 10 screening centers between November 1993 and July 2001 who were randomly assigned to annual PSA screening for 6 years and DRE for 4 years (38,340 men) or usual care (38,345 men), which sometimes included opportunistic screening in the local communities. All prostate cancer incidents and deaths through 13 years of follow-up or through December 31, 2009 were ascertained.

The 13-year follow-up analysis reports 45% of men in the PLCO trial had at least one PSA test in the 3 years prior to randomization. PSA screening in the usual care arm was estimated to be as high as 52% by the end of the screening period. The intensity of PSA screening in the usual care arm was estimated to be half that in the intervention arm. Stage-specific treatment between the two arms was similar.[49]

The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to evaluate the effect of screening with PSA testing on death rates from prostate cancer. Through registries in seven European countries, investigators identified 182,000 men between the ages of 50 and 74 years for inclusion in the study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006.

Recruitment and randomization procedures differed among countries and were developed in accordance with national regulations. In Finland, Sweden, and Italy, the trial subjects were identified from population registries and were randomly assigned to the trials before written informed consent was provided. In the Netherlands, Belgium, Switzerland, and Spain, the target population was also identified from population lists, but when the men were invited to participate in the trial, only those who provided consent were randomly assigned.

In the screening group, 82% of men accepted at least one offer of screening. With 14 years of data, and a median follow-up of 9 years, there were 5,990 prostate cancers diagnosed in the screening group and 4,307 in the control group, corresponding to a cumulative incidence of 8.2% and 4.8%, respectively. There were 214 prostate-cancer deaths in the screening group and 326 prostate cancer deaths in the control group in the core age group. The unadjusted rate ratio for death from prostate cancer in the screening group was 0.80 (95% CI, 0.67–0.95); after adjustment for sequential testing with alpha spending due to two previous interim analyses (based on Poisson regression analysis), the rate ratio was 0.80 (95% CI, 0.65–0.98). The rates of death in the two study groups began to diverge after 7 to 8 years and continued to diverge further over time.

The absolute difference between the screening and control groups was 0.71 prostate-cancer deaths per 1,000 men. Thus, to prevent one prostate-cancer death, the number of men who would need to be screened would be 1,410. The additional prostate cancers diagnosed by screening resulted in an increase in cumulative incidence of 34 per 1,000 men, so that 48 additional subjects would need to be treated to prevent one death from prostate cancer. Thus, PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis.[50]

Important information that was not reported includes the contamination rate in the control group, and the treatment administered to the prostate cancer cases by stage and by randomly assigned group. Incompleteness of data is also a concern because it appears that several of the participating countries have not yet provided data beyond the 10-year point at which the major effect appears to occur. Longer follow-up will be needed to determine the final results of this trial.

While the ERSPC demonstrated a 29% relative reduction in mortality from prostate cancer among men who were screened at 4-year intervals, there were associated harms from overdiagnosis and long-term treatment effects. Microsimulation Screening Analysis (MISCAN) was used to estimate the quality-adjusted life-years (QALYs) associated with annual PSA screening,[51] based on results from the ERSPC trial. Health states considered in the analysis of QALYs included biopsy, cancer diagnosis, radiation therapy, radical prostatectomy, active surveillance, postrecovery period, palliative therapy and terminal illness. Adverse effects considered included overdiagnosis and various degrees of incontinence and erectile dysfunction. The model predicted that annual screening of 1,000 men aged 55 to 69 years would lead to nine fewer deaths from prostate cancer (98 men screened to prevent one prostate cancer death). Overall, 73 life-years would be gained, but QALYs gained was only 56 life-years on average with a range of -21 to 97 life-years. Screening men aged 55 to 74 years increased life-years gained but resulted in the same number of QALYs on average (56 life-years).[51]

The Finnish Randomized Screening Trial is the largest component of the multicenter ERSPC consortium. Eighty thousand one hundred forty-four men born between 1929 and 1944 were identified from the Finnish Population Registry. Men with a previous prostate cancer diagnosis were excluded. Thirty one thousand eight hundred sixty-six men were randomly assigned to the screening arm (SA) and the remaining 48,278 men were randomly assigned to the control arm (CA). Randomization occurred annually from 1996 to 1999 (at ages 55, 59, 63, or 67 years at entry, which led to a similar age distribution in both arms). Men randomly assigned to the CA were not contacted. Men randomly assigned to the SA were invited to an initial screen, and if living in the study area and not already diagnosed with prostate cancer, were invited to second and third screenings at 4 and 8 years after randomization. Men with a PSA of 4.0 ng/mL or higher were referred to a local urological clinic for diagnosis. Men with a PSA of 3.0 to 3.99 ng/mL were referred to further testing. Median follow-up in both arms was 10.8 years. The screening arm had a nonstatistically significant reduction in prostate cancer mortality, based on an analysis of those who were invited to be screened. The hazard ratio between trial arms was 0.85 (95% CI, 0.69–1.04; P = .10). No screening effect was seen in all-cause mortality. Treatment differed between the two arms within each risk category. In all risk categories, radical prostatectomy was more common in the SA (statistically significant at P < .05 for moderate- and high-risk cancers) and radiation and endocrine treatment were more common in the CA (statistically significant at P < .05 for radiation in the moderate-risk category and for both radiation and endocrine treatment in the high-risk category). It was unknown whether this affected mortality. Contamination in the CA was not measured.[52]

Possible harms included overdiagnosis, which was estimated at 30% on the basis of excess cases in the SA if the cumulative risk of prostate cancer had been the same as the CA.[52]

The Goteborg (Sweden) trial is a prospective randomized trial of 20,000 men born between 1930 and 1944. Data from participants born between 1930 and 1939 is used in the pooled ERSPC data. Recently, data with up to 14 years of follow-up were reported. Of the screened group, 12.7% was diagnosed with prostate cancer versus 8.2% of the control group. The absolute risk of prostate death was 0.9% in the control group and 0.5% in the screening group (95% CI, 0.17–0.64). This is a 44% RR reduction in prostate-cancer mortality (95% CI, 0.28–0.68; P = .0002). Of note, the number of deaths from all causes was equal in the intervention group and the control group. The authors estimated that 12 men needed to be diagnosed and treated to prevent one death.[53]

The Norrkoping study (Sweden) is a population-based nonrandomized trial of prostate cancer screening. All men aged 50 to 69 years living in Norrkoping, Sweden in 1987 were allocated to either invited (every sixth man allocated to invited group) or not-invited groups. The 1,494 men in the invited group were offered screening every 3 years from 1987 to 1996. The first two rounds were by DRE; the last two rounds by both DRE and PSA. About 85% of men in the invited group attended at least one screening; contamination by screening in the not-invited group (n = 7,532) was thought to be low. After 20 years of follow-up, the invited group had a 46% relative increase in prostate cancer diagnosis. Over the period of the study, 30 men (2%) in the invited group died of prostate cancer, compared with 130 (1.7%) men in the not-invited group. The RR of prostate cancer mortality was 1.16 (95% CI, 0.78–1.73). This nonstatistically significant finding provides no evidence that screening leads to a reduction in prostate cancer mortality, even after 20 years of follow-up.[54]

Because the efficacy of screening depends on the effectiveness of management of screen-detected lesions, trials of treatment efficacy in early-stage disease are relevant to the issue of screening. The Prostate Intervention Versus Observation Trial (PIVOT) is the only published trial conducted in the PSA era that directly compared radical prostatectomy with watchful waiting.[55] From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer were randomly assigned to one of the two management strategies. About 50% of the men had nonpalpable, screen-detected disease. After a median follow-up of 10 years (maximum up to about 15 years), there was no statistically significant difference in overall or prostate-specific mortality. (Refer to the Treatment Option Overview section in the PDQ summary on Prostate Cancer Treatment for a more detailed description of the study and results.)

Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer

As noted above, various approaches aimed at improving the performance of PSA in early cancer detection have been tested. None are clearly more accurate than total serum PSA levels, but these approaches are discussed below.

Prostate cancer gene 3 (PCA3)

PCA3 was approved by the U.S. Food and Drug Administration in early 2012, with the intended use to improve the selection of men with a prior negative biopsy for an elevated PSA for whom a repeat biopsy is being considered for a persistently elevated PSA. This test is performed in a urine sample collected after an "attentive" DRE (several strokes applied firmly to the prostate to right and left prostatic lobes). Using a threshold value of 60, this test enhances the detection of prostate cancer while reducing the number of biopsies in men who will ultimately have a negative biopsy.[56]

Complexed PSA and percent-free PSA

Serum PSA exists in both free form and complexed to a number of protease
inhibitors, especially alpha-1-antichymotrypsin. Assays for total PSA measure
both free and complexed forms. Assays for free PSA are available. Complexed
PSA can be found by subtracting free PSA from the total PSA. Several studies have
addressed whether complexed PSA or percent-free PSA (ratio of free to total)
are more sensitive and specific than total PSA. One retrospective study
evaluated total PSA, free/total, and complexed PSA in a group of 300 men, 75 of
whom had prostate cancer. Large values of total, small values of free/total,
and large values of complexed PSA were associated with the presence of cancer; the
authors chose the cutoff of each measure to yield 95% sensitivity and found
estimated specificities of 21.8%, 15.6%, and 26.7%.[57] The preponderance of evidence concerning the utility of complexed and percent-free PSA is not clear, however, total PSA remains the standard.

A number of authors have considered whether complexed PSA or percent-free PSA
in conjunction with total PSA can improve the latter’s sensitivity. Of special
interest is the gray zone of total PSA, the range from 2.5 ng/mL to 4.0 ng/mL. A
meta-analysis of 18 studies addressed the added diagnostic benefit of percent-free PSA. There was no uniformity of cutoff among these studies. For cutoffs
ranging from 8% to 25% (free/total), sensitivity/specificity ranged from about
45%/95% to 95%/15%.[58]

Percent-free PSA may be related to biologic activity of the tumor. One study
compared the percent-free PSA with the pathologic features of prostate cancer
among 108 men with clinically localized disease who ultimately underwent
radical prostatectomy. Lower percent-free PSA values were associated with
higher risk of extracapsular disease and greater capsular volume.[59] Similar
findings were reported in another large series.[60]

Third-generation PSA

The third-generation (ultrasensitive) PSA test is an enzyme immunometric assay intended strictly (or solely) as an aid in the management of prostate cancer patients. The clinical usefulness of this assay as a diagnostic or screening test is unproven.[61,62]

PSA density

Because larger prostates caused by increased amounts of transition-zone
hyperplasia are known to be associated with higher serum PSA levels, reports
have suggested indexing PSA to gland volume, using a measure known as PSA
density. PSA density is defined as serum PSA divided by gland volume.
Generally, ultrasound is used to measure gland volume. While early studies
suggested that this measure may discriminate between patients with cancer and
those with benign disease,[63] subsequent evaluations have failed to confirm
any clinically useful association.[64,65]

PSA density of the transition zone

PSA
density of the transition zone (serum PSA divided by the volume of the
transition zone) has been suggested to better adjust for benign sources of PSA.
One study prospectively evaluated 559 men with PSA levels between 4.0 ng/mL and 10.0
ng/mL. A total of 217 of these men were ultimately found to have prostate
cancer; of all PSA variants analyzed, percent-free PSA and PSA density of
the transition zone were found to have the best predictive value (area under
the receiver operator curve values of 0.78 and 0.83).[66]
Another study also found that PSA density of the transition zone had superior
performance characteristics. In this study of 308 volunteers undergoing
first-time screening, it was reported that the combination of percent-free PSA
(<20%) and PSA density of the transition zone resulted in elimination of 54.2%
of biopsies that ultimately proved to be benign.[67]

Age-adjusted PSA

Many series have noted that PSA levels increase with age, such that men without
prostate cancer will have higher PSA values as they grow older. One study
examined the impact of the use of age-adjusted PSA values during screening and
estimated that it would reduce the false-positive screenings by 27% and
overdiagnosis by more than 33% while retaining 95% of any survival advantage
gained by early diagnosis.[68] While age adjustment tends to improve
sensitivity for younger men and specificity for older men, the trade-off in
terms of more biopsies in younger men and potentially missed cancers in older
men has prevented uniform acceptance of this approach.

PSA velocity

A study using frozen serum from 18 patients concluded that an annual rise of
PSA level of 0.8% ng/mL warranted a prostate biopsy.[69] In a follow-up study
that used serum collected serially from men without known prostate cancer (two
groups with benign prostatic hyperplasia, one diagnosed by histology and the
other clinically, both with PSA levels no higher than 10 ng/mL, and a
third group with no more than one PSA exceeding 10 ng/mL), it was reported that
averaging three PSA changes measured at 2-year intervals could be useful for cancer
discrimination, while changes measured at 3-month or 6-month intervals were volatile
and nonspecific, perhaps because of a biologic fluctuation of PSA that may be
as high as 30%.[42,70] One study followed 1,249 men screened by PSA and
concluded that patients with a 20% annual increase in their PSA level should
undergo further evaluation.[71]

A study specifically tested whether total PSA velocity (tPSAv) improves the accuracy of total PSA level (tPSA) to predict long-term risk of prostate cancer. In the 1974 to 1986 Swedish Malmo Preventive Medicine cardiovascular risk study, 5,722 men younger than 51 years gave two blood samples about 6 years apart. Four thousand nine hundred-seven of the archived plasma samples were analyzed for tPSA. Prostate cancer was subsequently diagnosed in 443 (9%) of the men via the Swedish National Cancer Registry through December 31, 2003. Cox proportional hazards regression was used to evaluate tPSA and tPSAv as predictors of prostate cancer. Predictive accuracy was assessed by the concordance index (similar to the area under the receiver operating characteristic).[72]

The median time from the second blood draw to cancer diagnosis was 16 years. Median follow-up for men not diagnosed with prostate cancer was 21 years. PSA assays were done in plasma stored under conditions that preserved the integrity of PSA. TPSA and tPSAv were highly correlated. Both tPSA and tPSAv were associated with prostate cancer in univariate models (P < .001). Men subsequently diagnosed with prostate cancer have increased tPSA and increased tPSAv up to 20 years before diagnosis. Overall predictive accuracy of tPSA plus tPSAv was equivalent to tPSA alone (concordance index: 0.771 tPSA alone; 0.712 tPSAv alone; 0.771 tPSAv added to tPSA). TPSAv did not aid long-term prediction of cancer in early middle-aged men.[72]

In the PCPT, full ascertainment was attempted, regardless of PSA value; PSA velocity added no independent value to the prediction of prostate cancer after adjustment for family history, age, race/ethnicity, PSA, and history of prostate biopsy. For this reason, in the PCPT risk calculator, PSA velocity is not an included variable.[73]

Alteration of PSA cutoff level

A number of authors have explored the possibility of using PSA levels
lower than 4.0 ng/mL as the upper limit of normal for screening examinations.
One study screened 14,209 white and 1,004 African American men for prostate
cancer using an upper limit of normal of 2.5 ng/mL for PSA. A major
confounding factor of this study was that only 40% of those men in whom a
prostate biopsy was recommended actually underwent biopsy. Nevertheless, 27%
of all men undergoing biopsy were found to have prostate cancer.[37] Several
collaborating European jurisdictions are conducting prostate cancer screening
trials, Rotterdam (the Netherlands) and Finland among them. In
Rotterdam, data for 7,943 screened men between the ages of 55 and 74 years have been
reported. Of the 534 men who had PSA levels between 3.0 ng/mL and 3.9 ng/mL, 446
(83.5%) had biopsies and 96 (18%) of these had prostate cancer. In all, 4.7% of
the screened population had prostate cancer.[74] In Finland, 15,685 men were
screened and 14% of screened men had PSA levels of at least 3.0 ng/mL. All
men with PSAs higher than 4.0 ng/mL were recommended to diagnostic follow-up by
DRE, ultrasound, and biopsy; 92% complied, and 2.6% of the
15,685 men screened were diagnosed with prostate cancer. Of the 801 men with
screening PSAs between 3.0 ng/mL and 3.9 ng/mL (all biopsied), 22 (3%) had cancer. Of
the 1,116 men with screening PSAs between 4.0 ng/mL and 9.9 ng/mL, 247 (22%) had cancer; of the 226 men with screening PSAs of at least 10 ng/mL, 139 (62%) had cancer.[75]
Several factors could have contributed to these differences, including
background prostate cancer prevalence, background screening levels, and details
regarding diagnostic follow-up practices; the necessary comparative data are
not available.

Another study adopted a change in the PSA cutoff to a level of 3.0 ng/mL to
study the impact of this change in 243 men with PSA levels between 3.0 ng/mL and 4.0
ng/mL. Thirty-two of the men (13.2%) were ultimately found to have prostate
cancer. An analysis of radical prostatectomy specimens from this series found
a mean tumor volume of 1.8 cc (range, 0.6–4.4). The extent of disease was
significant in a number of cases, with positive margins in five cases and pathologic pT3
disease in six cases.[39]

Frequency of screening

The optimal frequency and age range for PSA (and DRE) testing are
unknown.[68,76,77] Cancer detection rates have been reported to be similar for intervals of 1 to 4 years.[78] With serial annual screening in the PLCO trial, 8% of men with baseline PSA lower than 1 ng/mL had a prostate cancer diagnosis within 2 years.[79] In the same trial, 2-year intervals in screening produced average delays of 5.4 to 6.5 months, while 4-year screening intervals produced average delays of 15.6 months (baseline PSA < 1 ng/mL) to 20.9 months (baseline PSA 3–4 ng/mL).[79] While the authors caution that an optimal prostate screening frequency cannot be determined from these data, they conclude that among men who choose to be screened, these data may provide a context for determining a PSA screening schedule.

A report from the ERSPC trials demonstrated that while more frequent screenings lead to more diagnosed cancers, the detection rates for aggressive interval cancers was very similar with the different screening intervals in place in the two countries reporting (0.11 with a 4-year interval in Rotterdam and 0.12 with a 2-year interval in Gothenburg). The report suggests that mortality outcomes from the ERSPC (2- and 4-year intervals) and PLCO (1-year interval) trials should facilitate a more reliable assessment of the benefits and costs of different screening intervals.[80]

Types of Tumors Detected by Prostate Cancer Screening

Of serious concern with regard to prostate cancer screening is the high
background histologic prevalence of the disease. It has been demonstrated that
a considerable fraction (approximately one-third) of men in their fourth and
fifth decades have histologically evident prostate cancer.[81] Most of these
tumors are well-differentiated and microscopic in size. Conversely, evidence
suggests that tumors of potential clinical importance are larger and of higher
grade.[82] Since the inception of PSA screening, several events have occurred:
(1) a contemporaneous but unrelated decrease in detections of transition-zone
tumors caused by a fall in the number of transurethral resections of the
prostate due to the advent of effective treatment for benign prostatic
hyperplasia (including alpha blockers and finasteride); and (2) an increase in
detection of peripheral-zone tumors due to the incorporation of TRUS-guided prostate biopsies. Because transition-zone tumors are
predominantly low volume and low grade and because peripheral-zone tumors have a
preponderance of moderate-grade and high-grade disease, the proportion of higher grade tumors detected by current screening practices has increased
substantially. A Detroit study found that between 1989 and 1996,
poorly differentiated tumors remained stable and well-differentiated tumors
fell in frequency while moderately differentiated disease increased in
frequency. The largest rise in incidence was in clinically localized
disease.[83] It is now known that systematic changes to the histological interpretation of biopsy specimens by anatomical pathologists has occurred during the PSA screening era (i.e., since about 1985) in the United States.[84] This phenomenon, sometimes called “grade inflation,” is the apparent increase in the distribution of high-grade tumors in the population over time but in the absence of a true biological or clinical change. It is possibly the result of an increasing tendency for pathologists to read tumor grade as more aggressive.[85]

Prostate biopsies in a small percentage of men will demonstrate prostatic intraepithelial neoplasia (PIN). High-grade PIN is not cancer but may predict an increased risk for prostate cancer. PSA does not appear to be elevated with PIN.[86,87]

Physician Behaviors Related to Screening

A variety of variables affect the likelihood of a recommendation for prostate
cancer screening from a physician. In Washington State, 1,369
primary care physicians were surveyed to determine patterns
of PSA screening recommendations. Of the 714 respondents, 68% routinely recommended PSA
screening. The survey results suggest that gender (male), age (medical school
graduation before 1974), and mode of reimbursement (fee for service) all
increase the likelihood of PSA screening recommendations among this population.[88]

While two large randomized clinical trials are under way to assess
whether early detection of prostate cancer can reduce mortality from the
disease,[89,90] a Canadian trial has been reported to have
been performed in a randomized prospective manner. In this study, 46,486 men
identified from the electoral rolls of Quebec City and its metropolitan area
were randomly assigned to be either approached or not approached for PSA and DRE screening. A
total of 31,133 men were randomly assigned to screening, while a total of 15,353 were
randomly assigned to observation. (It appears that these men were unaware that they
had been enrolled in a randomized clinical trial.) A notable difference from other
screening studies was that a PSA of 3.0 ng/mL was used to determine whether
further evaluation was warranted. In this study (in which the patient numbers have been variously reported by the authors) of the 31,133 men who were
randomly assigned to screening, 7,348 actually underwent screening while 23,785 did
not. Of the 15,353 who were randomly assigned to observation, 1,122 actually underwent
screening while 14,231 did not. Two hundred-seventeen deaths were noted
among the 38,016 men who did not undergo screening, compared with only 11 deaths
among the 8,470 men who underwent screening. Using an intention-to-treat
analysis based on the study arm to which an individual was originally
assigned, however, no difference in mortality was seen (there were 75 deaths
among the 15,353 men who were randomly assigned to observation compared with 153 deaths
among the 31,133 men randomly assigned to screening [RR, 1.085]). Because of noncompliance, this
study does not answer the question of whether early detection with PSA
will reduce prostate cancer mortality.[91]

Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality

While DRE has been a staple of medical practice for many decades, PSA did not
come into common use until the late 1980s for the early diagnosis of prostate
cancer. Following widespread dissemination of PSA testing, incidence rates rose abruptly. In a study of Medicare
beneficiaries, a first-time PSA test was associated with a 4.7% likelihood of a
prostate cancer diagnosis within 3 months. Subsequent tests were associated
with statistically significant lower rates of prostate cancer diagnosis.[92]

In an examination of trends of prostate cancer detection and diagnosis among
140,936 white and 15,662 African American men diagnosed with prostate cancer
between 1973 and 1994 in the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) database, substantial changes were found
beginning in the late 1980s as use of PSA diffused through the United States;
age at diagnosis fell, stage of disease at diagnosis
decreased, and most tumors were noted to be moderately differentiated. For
African American men, however, a larger proportion of tumors were poorly
differentiated.[93]

Since the outset of PSA screening beginning around 1988, incidence rates
initially rose dramatically and fell, presumably as the fraction of the
population undergoing their first PSA screening initially rose and subsequently
fell. There has also been an observed decrease in mortality rates. In Olmsted
County, Minnesota, age-adjusted prostate cancer mortality rates
increased from 25.8 per 100,000 men from 1980 to
1984 to a peak of 34 per 100,000 from 1989 to 1992; rates subsequently
decreased to 19.4 per 100,000 from 1993 to 1997.[94] Similar observations
have been made elsewhere in the world,[95,96] leading some to hypothesize that
the mortality decline is related to PSA testing. In Quebec, Canada,
however, examinations of the association between the size of the rise in
incidence rates (1989–1993) and the size of the decrease in mortality
rates (1995–1999), by birth cohort and residential grouping, showed no
correlation between these two variables.[96] This study suggests that, at least
during this time frame, the decline in mortality is not related to widespread PSA
testing.

Cause-of-death misclassification has also been studied as a possible explanation for changes in prostate cancer mortality. A relatively fixed rate was found at which individuals who have been diagnosed with prostate cancer are mislabeled as dying from prostate cancer. As such, the substantial increase in prostate cancer diagnoses in the late 1980s and early 1990s would then explain the increased rate of prostate cancer death during those years. As the rate of prostate cancer diagnosis fell in the early 1990s, this reduced rate of mislabeling death due to prostate cancer would fall, as would the overall rate of prostate cancer death.[97] Since the evidence in this respect is inconsistent, it remains
unclear whether the causes of these mortality trends are chance, misclassification, early detection,
improved treatments, or a combination of effects.

The incidence of distant-stage prostate carcinoma was relatively flat until 1991 and then started declining rapidly. This decline probably was caused by the shift to earlier stage disease associated with the rapid dissemination of PSA screening. This stage shift can have a fairly sizable and rapid impact on population mortality, but it is possible that other factors such as hormonal therapy are responsible for much of the decline in mortality. Ongoing randomized clinical trials in the United States and Europe are designed to determine whether a mortality benefit is associated with PSA screening.[98]

The Gleason score is an important prognostic measure relying on the pathologic assessment of the architectural growth patterns of prostate biopsy. The Gleason grading system assigns a grade to each of the two largest areas of prostate cancer in the tissue samples. A sampling of eight or more biopsy cores improves the pathological grading accuracy.[99] Grades range from 1 to 5, with 1 being the most differentiated and 5 the least differentiated. Grade 3 tumors seldom have associated metastases, but metastases are common with grade 4 or grade 5 tumors. The two grades are added together to produce a Gleason score. A score of 2 to 4 is rarely given, 5 to 6 is low grade, 7 is intermediate grade, and 8 to 10 is high grade. The overall rate of concordance between original interpretations and review of the needle biopsy specimens has been reported to be 60%, with accuracy improving with increased tumor grade and percentage of tumor involvement in the biopsy specimen.[100]

As of 2005, approximately 90% of prostate cancers detected are clinically localized and have more favorable tumor characteristics or grades than the pre-PSA screening era.[101] A retrospective population-cohort study using the Connecticut Tumor registry reviewed the mortality probability from prostate cancer given the patient’s age at diagnosis and tumor grade.[102] Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. This study was initiated before the PSA screening era. Transurethral resection or open surgery for benign prostatic hyperplasia identified 71% of the tumors incidentally.
The prostate cancer mortality rate was 33 per 1,000 person-years during the first 15 years of follow-up (95% CI, 28–38) and 18 per 1,000 person-years after 15 years of follow-up (95% CI, 10–29). Men with low-grade prostate cancers had a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2 to 4; six deaths per 1,000 person-years; 95% CI, 2–11). Men with high-grade prostate cancers had an increased probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8 to 10, 121 deaths per 1,000 person-years; 95% CI, 90–156). Men with tumors that had a Gleason score of 5 or 6 had an intermediate risk of prostate cancer death. The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis.[102]

Simulation Models

A computer simulation model has been developed to analyze the trends in
prostate cancer detection (PSA screening beginning in approximately 1988) to
compare these trends with the reported fall in prostate cancer deaths observed
between 1992 and 1994. The level of screening efficacy was hypothesized to be
similar to those postulated in the PLCO. The changes in prostate cancer mortality could not be explained
entirely by PSA screening alone.[103]

Decision analyses using the Markov model yield variable treatment outcomes because of the uncertainty regarding metastatic rates expected for prostate cancer and
uncertainty about treatment efficacy.[104-106] A review of 59,876 men with
prostate cancer diagnosed between 1983 and 1992 and registered by the SEER
registries, however, shows that treatment of men with poorly differentiated and
moderately differentiated disease is associated with an improved survival rate,
compared with observation.[107] It is not known to what degree this can be
attributed to treatment effect as opposed to other factors such as a
preponderance of relatively healthy patients in the treated group. The
information from Swedish studies of expectant therapy lead to different
conclusions depending on methodology and populations used in analysis.[108]

Simulation modeling from the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network (CISNET) program suggests that changes in prostate cancer treatment explain a portion of the drop in prostate cancer mortality but that most of the decline is likely the result of other factors such as screening or improvements in disease management after primary therapy.[109]

A simulation model based on available evidence suggests that if there is a
benefit to screening, this benefit decreases with age.[110] No trial of
prostate cancer screening in which the intervention arms were analyzed as
randomized (analogous to an intention-to-treat analysis in a treatment trial)
has been reported. There is insufficient evidence on which to decide the
efficacy of TRUS and serum tumor markers (including PSA) for
routine screening in asymptomatic men.[104,111]

Providing Information to the Public, to Patients, and to Their Families

While awaiting results of current studies, physicians and men (and their partners) are faced with the dilemma of whether to recommend or request a screening test. A qualitative study undertaken on focus groups of men, physician experts, and couples with screened and unscreened men has explored what information may help to inform a man undertaking a decision regarding PSA screening.[112] At a minimum, men should be informed about the possibility that false-positive or false-negative test results can occur, that it is not known whether regular screening will reduce the number of deaths from prostate cancer, and that among experts, the recommendation to screen is controversial. The PLCO-1, which is now closed to accrual, is following participants to test the effect of early detection by DRE and PSA on reducing mortality. A trial of screening is also being performed in Europe.[89,113]

Evidence of Harms

Any potential benefits derived from screening asymptomatic men need to be weighed against the harms of screening and diagnostic procedures and treatments for prostate cancer.

Whatever the screening modality, the screening process itself can lead to psychological effects in men who have a prostate biopsy but do not have prostate cancer. One study of these men at 12 months after their negative biopsy who reported worrying that they may develop cancer (P < .001), showed large increases in prostate-cancer worry compared with men with a normal prostate-specific antigen (PSA) (26% vs. 6%).[1] In the same study, biopsied men were more likely than those in the normal PSA group to have had at least one follow-up PSA test in the first year (73% vs. 42%; P < .001), more likely to have had another biopsy (15% vs. 1%; P < .001), and more likely to have visited a urologist (71% vs. 13%; P < .001).

Three cohort studies in Sweden and in the United States linked databases to examine the association between new diagnosis of prostate cancer with cardiovascular events/death or with suicide. One Swedish study found that in the first year after the diagnosis of prostate cancer, the risk of death from cardiovascular disease (CVD) was increased in men diagnosed with prostate cancer compared with men who were not diagnosed with prostate cancer (relative risk [RR] = 1.9; 95% confidence interval [CI], 1.9–2.0; adjusted for age, calendar time period, and time since diagnosis). The risk of death from CVD was highest in the first week after diagnosis (RR = 11.2; 95% CI, 10.4–12.1) and was also higher in younger men (age < 54 years). These risks were less in men diagnosed in the most recent time periods. Also in the first year after diagnosis, the risk of committing suicide was higher for men who had been diagnosed with prostate cancer (RR = 2.6; 95% CI, 2.1–3.0; adjusted for age, calendar time period, marital status, educational level, and history of psychiatric hospitalization). Again, this was highest in the first week after diagnosis (RR = 8.4; 95% CI, 1.9–22.7).[2] A second Swedish study largely confirmed these findings.[3]

The U.S. cohort study explored the association between prostate cancer diagnosis and CVD mortality or suicide in men diagnosed with prostate cancer compared with population-level expected rates during three different time periods (pre-PSA, peri-PSA, and post-PSA). For CVD mortality, the standardized mortality ratio (SMR) was elevated for men diagnosed with prostate cancer in the first month after diagnosis in all time periods (overall SMR = 2.05; 95% CI, 1.89–2.22), but decreased in later months during the first year (decreasing to < 1.0 in the PSA time period). This association was not changed to an important degree by age, race, or tumor grade. SMRs were higher for nonmarried men, for men who lived in lower educational status or higher poverty counties, and for men with metastatic disease at diagnosis. Also, in the first 3 months after diagnosis, the SMR for suicide was higher in men with prostate cancer (SMR = 1.9; 95% CI, 1.4–2.6). In months 4 to 12, the SMR was lower but still greater than 1.0. The SMR for suicide, however, was only greater than 1.0 in the pre-PSA and peri-PSA time periods, but not in the post-PSA time period. SMR was higher for nonmarried men but did not vary by education or poverty.[4]

These data lend credence to the concern that overdiagnosis of prostate cancer due to screening could lead to an increased risk of CVD mortality or suicide.

While there is no literature suggesting serious complications of digital rectal examination (DRE) or transrectal sonography, and the harms associated with venipuncture for PSA testing can be regarded as trivial, prostatic biopsies are associated with important complications. Transient fever, pain, hematospermia, and hematuria are all common, as are positive urine cultures.[5-7] Sepsis occurs in approximately 0.4% of cases.[6,8]

Long-term complications of radical prostatectomy include urinary incontinence, urethral stricture, erectile dysfunction, and the morbidity associated with general anesthesia and a major surgical procedure. Fecal incontinence can also occur. The associated mortality rate is reported to be 0.1% to 1%, depending on age. In the population-based Prostate Cancer Outcomes Study, 8.4% of 1,291 men were incontinent and 59.9% were impotent at 18 or 24 months following radical prostatectomy. More than 40% of men reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age, with younger men relatively less affected.[8,9]

Definitive external-beam radiation therapy can result in acute cystitis, proctitis, and sometimes enteritis. These are generally reversible but may be chronic. In the short-term, potency is preserved with irradiation in most cases but may diminish over time. A systematic review of evidence of complications of radiation therapy shows that 20% to 40% of men who had no erectile dysfunction before treatment developed dysfunction 12 to 24 months afterwards. Furthermore, 2% to 16% of men who had no urinary incontinence before treatment developed dysfunction 12 to 24 months afterward, and about 18% of men had some bowel dysfunction 1 year after treatment. The magnitude of effects of brachytherapy has not been determined, but the spectrum of complications are similar.[10] Radiation to the prostate has been reported to increase the risk of secondary malignancies, most notably of the rectum and bladder. While the relative risk in a large Surveillance, Epidemiology and End Results (SEER)-based study was 1.26 (95% CI, 1.21–1.30), the absolute increase in risk is low. The same review of evidence found hormone therapy with luteinizing hormone-releasing hormone (LHRH) agonists reduces sexual function by 40% to 70%, and is associated with breast swelling in 5% to 25% of men. Hot flashes occur in 50% to 60% of men taking LHRH agonists.[8] (Refer to the PDQ summary on Prostate Cancer Treatment for more information.)

The question of whether prostate cancer treatment contributes to symptoms among screened prostate cancer survivors was addressed in an analysis from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The
randomized controlled PLCO analysis compared 529 prostate cancer survivors, 5 to 10 years postdiagnosis, with 514 noncancer controls, regarding prostate cancer-specific symptomatology. There was poorer sexual and urinary function among prostate cancer survivors compared with noncancer controls, suggesting that these symptoms are related to prostate cancer treatment and not aging or comorbidities.[11]

Screening has increased the incidence of prostate cancer. In the current medical climate, most early-stage prostate cancers are treated by radical surgery or irradiation with intent to eradicate the pathology. There is evidence that not all patients diagnosed with prostate cancer as a consequence of screening are in immediate need of curative treatment. Death from other causes often occurs before screen detected, localized, and well-differentiated malignancies affect the survival of these patients. To avoid overtreatment and consequent morbid events, active surveillance (AS) is an emerging strategy applicable in these kinds of cases wherein curative treatment is delayed pending objective medical evidence of disease progression.

The effectiveness of AS was retrospectively investigated in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Data from 577 men diagnosed with prostate cancer as a consequence of periodic screening between 1994 and 2007 at a mean age of 66.3 years in four participating clinical centers in the Netherlands, Sweden, and Finland were evaluated. Selection criteria for inclusion in the analysis were:

PSA less than or equal to 10 ng/mL.

PSA density less than 0.2 ng/mL.

Stage T1C/T2.

Gleason score less than or equal to 3 + 3 = 6.

No more than two positive biopsy cores.

Men with positive lymph nodes or distant metastases at the time of diagnosis were excluded from the analysis. These are the same thresholds being applied in the (as yet unreported) prospective Prostate Cancer Research International: Active Surveillance study on AS originating from ERSPC and in the (also unreported) protocol-based prospective study of AS in Canada.

The mean follow-up time for the 577 men in the retrospective assessment was 4.35 years (0–11.63 years). The calculated 10-year prostate cancer-specific survival rate was 100%. The overall 10-year survival rate was 77%. The calculated 10-year deferred treatment-free survival rate was 43%.

After 7.75 years, 50% of men had received treatment. The median treatment-free survival was 2.5 years. Men treated during follow-up were slightly younger at diagnosis than men remaining untreated (64.7 years vs. 67.0 years; P < .001). Of the 110 men shifting to active treatment despite favorable PSA levels and PSA doubling times, DRE was known in 53 of the men and played a role in nine of them, whereas rebiopsies were known in 27 of the men and played a role in none of them. On the basis of PSA characteristics, 1.9% of patients who remained untreated may have been better candidates for active treatment, while 55.8% of men who received active treatment were not obvious candidates for radical treatment and neither DRE nor rebiopsy explained the discrepancy. Factors like anxiety and urologic complaints may have been more explanatory, but the data were not available.

The authors conclude that their data confirm prior studies' findings, that many screen-detected prostate cancers may be actively followed (e.g., AS), and curative treatment delayed, thereby delaying or avoiding the morbid consequences of radical therapy without diminishing survival. The authors also note that a considerable fraction of men do not comply with the AS regimen apparently for psychological reasons, and AS often results in delay, not avoidance, of radical therapy.

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